Abstract Vasculonics, an Indiana-based small business is developing a novel approach to reduce progression of pulmonary arterial hypertension (PAH). Vasculonics technology is a novel modulator of dimethylarginine dimethylaminohydrolase (DDAH) which reduces asymmetric dimethyl arginine (ADMA) and vascular pathology in PAH. High levels of ADMA and reduced DDAH occur in patients and preclinical models of PAH. In addition to reducing nitric oxide (NO) synthesis, high levels of ADMA induce mitochondrial dysfunction, cell death, inflammation and fibrosis. Persistent high ADMA levels can contribute to the progressive vascular remodeling observed in PAH. The proof of concept that restauration of DDAH is therapeutic has been achieved by overexpression of DDAH gene which lowered ADMA, improved endothelial function and modified the pathology in the lung. Vasculonics is developing a pharmacological approach using a small molecule modulator of DDAH to reduce pathological levels of ADMA and reduce the progressive vasculopathy in PAH. Vasculonics has identified VN-317 as a drug candidate which enhances transcription of DDAH-1 in a promoter-luciferase based screen. In a preclinical model of PAH, VN-317 has shown robust efficacy by reducing occlusion of lung arteries, and improving lung and cardiac functions. VN-317 is a novel molecule acting via a new mechanism for reducing vascular pathology in PAH. In order to advance VN- 317 to clinical phase, Vasculonics will complete the following aims in phase 1 SBIR. In aim 1 we will test the dose-dependent efficacy of VN-317 on reducing progression of PAH. In preliminary studies, VN-317 was tested in the rat model of MCT induced PAH when delivered at the time of disease onset. Therefore, we will test efficacy on disease progression in a highly rigorous Sugen hypoxia model. Treatment with VN-317 will begin 5 weeks after disease onset. Efficacy will be determined after 3 weeks by using the end points of pulmonary artery pressure, echocardiography, histology and markers of vascular remodeling. In Aim 2, we will test efficacy of VN-317 on top of a current vasodilator drug sildenafil to demonstrate its efficacy on disease progression in the settings similar to treatment in humans. The end points for efficacy in Sugen hypoxia model will be the same as listed in Aim 1. At the end of Phase I, Vasculonics will have confirmed efficacy of VN-317 in a model of PAH progression, and its efficacy on top of a vasodilator therapy. The Phase II efforts will focus on IND enabling CMC, pharmacokinetics and safety studies. A significant market exists for PAH therapy with an estimated value in excess of $4 billion.